PROJECT SUMMARY Non-alcoholic fatty liver disease (NAFLD) is a co-morbidity of obesity that is increasing in prevalence and now affects a quarter of the global population. Critically, there are currently no available therapeutics for NAFLD, making the need for a novel therapeutic that decreases hepatic triglycerides increasingly urgent. Fibroblast growth factor-21 (FGF21) is a liver-produced hormone that consistently decreases hepatic triglycerides when given pharmacologically and thus has gained tremendous interest as a potential therapeutic for NAFLD. Consequently, several pharmaceutical companies are actively developing FGF21-analogs. Indeed, a recent and exciting clinical trial found promising results of an FGF21-analog to ameliorate NAFLD. However, the mechanisms by which FGF21 decreases hepatic triglycerides is unclear. This presents a major obstacle in discovering new potential targets for the treatment of NAFLD, which remains exceedingly important. In light of recent evidence that FGF21 does not act directly on hepatocytes (or adipocytes, an important regulator of whole-body lipid metabolism) to decrease liver triglycerides, our overarching hypothesis is that FGF21 acts on the brain to decrease hepatic triglycerides via increased sympathetic drive to the liver. We will test this hypothesis by determining the sufficiency (Aim 1) and necessity (Aim 2) of FGF21 action in the brain to decrease hepatic triglycerides via increased sympathetic drive to the liver. Additionally, our preliminary data suggest that FGF21 acts in the suprachiasmatic nucleus (SCN) of the hypothalamus; thus, we will test the importance of this brain region to mediate FGF21?s hepatic effects. We will test these hypotheses using techniques including intracerebroventricular and intra-SCN cannulation, genetic knockdown models, site- specific stereotactic delivery of AAVs, and hepatic sympathectomy. Successful completion of these experiments will not only further our understanding of FGF21 and the role of the brain to regulate hepatic lipid metabolism, but will also provide new insights into potential targets for the treatment of NAFLD. Importantly, in addition to the experiments outlined in the Research Strategy, the present proposal includes wholistic training for scientific and professional development. This training will be facilitated by intentional mentorship by the sponsor and co-sponsor, professional development activities, and the outstanding facilities and expertise available at UC Davis. Together, the present proposal will aid in my preparation for my next career stage and advance me toward my long-term goal of becoming an academic scientist conducting translational research in the field of metabolism.